This on-going research, now in its fifteenth year of funding, has been concerned with developing transgenic and knockout mice to study the mechanisms of myocardial ischemia/reperfusion injury. Our research so far focussed on an important aspect of the injury, i.e., the role of reactive oxygen species (ROS) as second messenger, especially, Redox Signaling in cellular injury and survival. Having established that Redox Signaling plays a crucial role in repairing cells injured during ischemia and reperfusion, it appears to be quite appropriate to determine if such Redox Signaling is also operative for repairing cells in diseased myocardium. For this, we plan to choose the hearts in subjects affected by Metabolic Syndrome characterized by a group of metabolic risk factors including combination of medical disorders that increase the risk of developing cardiovascular disease, diabetes and obesity featuring hypertension, high cholesterol and insulin resistance. Our plan is to study by examining Redox Signaling in subjects suffering from metabolic syndrome by addressing the following Specific Aims: 1) examining imbalance in Redox homeostasis in the subjects from Metabolic Syndrome. Since such imbalance is expected to occur due to redox stress [NADH/NADPH imbalance], loss of redox proteins [Trx/Grx/Prdx], we propose to examine the changes in the profiles of redox regulated proteins and redox sensitive genes;2) studying the roles of major redox proteins, Trx, Grx, and Prdx using genetically engineered animals;3) determining the roles of Trx, Grx and Prdx by overexpressing these proteins through Redox Gene Therapy and examining myocardial protection in redox-gene overexpressed hearts;4) determining the role of Trx-binding protein (TBP), specifically, TBP-2 in metabolic syndrome using both transgenic animals and TBP-2 protein overexpressed hearts;5)studying the mechanisms of redox signaling by determining the generation of death signal by metabolic syndrome, its modification during ischemia/reperfusion and conversion of death signal into survival signal;. and 6) examining the role of PPAR and PPAR in redox regulation of metabolic syndrome-associated cardiac dysfunction i) using PPAR and/or PPAR knockout mice ii) overexpression of PPARS and iii) inhibiting PPARS with shRNAs. The ultimate goal of our study is to extend our recent findings of the redox signaling in the ischemic myocardium to the diseased hearts, such as those from obese subjects. PUBLIC HEALTH RELEVANCE: The ultimate goal of our proposed study is to extend our recent findings of the redox signaling in the ischemic myocardium to the diseased hearts, such as those from obese subjects. Obesity has become the leading metabolic disease, which poses a serious health problem throughout the world including United States. It is considered as a major risk factor associated with several degenerative diseases including coronary heart disease. The results of this study is likely to develop new treatment of obesity.